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Association of Schatzki Ring With Eosinophilic Esophagitis in Children

Nurko, Samuel*; Teitelbaum, Jonathan E.*; Husain, Khaled*; Buonomo, Carlo; Fox, Victor L.*; Antonioli, Donald; Fortunato, Christine*; Badizadegan, Kamran; Furuta, Glenn T.*

Journal of Pediatric Gastroenterology and Nutrition: April 2004 - Volume 38 - Issue 4 - p 436-441
Original Articles—Gastroenterology
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Objective: To describe the clinicopathologic characteristics of children with Schatzki ring and to determine if Schatzki ring is associated with eosinophilic esophagitis.

Methods: The authors report 18 adolescents with radiographically diagnosed Schatzki ring (SR). Their clinical and histologic characteristics were reviewed in a blinded fashion.

Results: The mean age of the patients was 15.8 ± 0.8 years and mean duration of symptoms was 2.6 ± 0.4 years. By histologic criteria, two groups of patients were defined. Eight had clinical and histologic criteria of eosinophilic esophagitis (EE) and 10 of peptic esophagitis. There were no differences in the symptoms or radiographic findings in the two groups. The SR was not identified by endoscopy in any EE patient and was identified in 70% of peptic esophagitis patients. Grossly apparent mucosal features associated with EE were significantly more common in those with EE. Those with peptic esophagitis had a significantly higher acid exposure than did those with EE (12.6 ± 2.9 v 2.0 ± 1.1%; P < 0.01) by esophageal pH probe. Patients with peptic esophagitis responded to proton pump inhibitors and/or dilatation, whereas those with EE did not have good response and required specific therapy for EE.

Conclusions: EE may play a role in the pathogenesis of some patients with SR.

Divisions of *Gastroenterology, †Pathology, and ‡Radiology, Children’s Hospital Boston, and Departments of Pediatrics, Pathology, and Radiology, Harvard Medical School, Boston, Massachusetts, U.S.A.

Received July 3, 2003; revised December 9, 2003; accepted December 18, 2003.

Address correspondence and reprint requests to Dr. Samuel Nurko, Division of Gastroenterology, Hunnewell Building, Ground Floor, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115 (e-mail: samuel.nurko@tch.harvard.edu).

Schatzki ring (SR) is a thin diaphragm-like circumferential fold of mucosa that protrudes into the lumen of the distal esophagus (1). It measures 1 to 2 mm in thickness and is located at the gastroesophageal squamocolumnar junction (2,3). Its prevalence ranges from 0.2% to 15% in the general population, depending on diagnostic techniques and diagnostic criteria (2,4,5). The prevalence in children is unknown, but very few pediatric cases have been reported (6)

The etiology and pathogenesis of SR are not well understood (2,3,7). Peptic inflammation is thought to be a contributing factor (8); however, prospective studies have documented an association with gastroesophageal reflux (GER) in fewer than two thirds of patients. Furthermore, not all patients experience a response to antireflux medication (2,3,5,6,8). These findings suggest that there may be additional pathogenic mechanisms.

Eosinophilic esophagitis (EE) is a disorder with symptoms similar to those described in patients with SR. Patients with EE typically report dysphagia and food impaction. The squamous epithelium contains numerous eosinophils in mucosal biopsy specimens from the proximal and distal esophagus. In addition, focal and diffuse esophageal narrowing consistent with esophageal stricture or small caliber esophagus can be seen (9–11). Recently, we identified several patients with EE who had radiographic evidence of SR. Because patients with EE have thickening of the esophageal wall (12), we hypothesized that the thickened mucosa, submucosa, and muscularis propria of patients with EE might protrude into the esophageal lumen, creating the appearance of SR. The aims of this study were to: (1) identify clinicopathologic features of children with SR, and (2) determine if SR is associated with EE.

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MATERIALS AND METHODS

Clinical Evaluation

The study was approved by the Committee on Clinical Investigation, Children’s Hospital Boston. Radiological records of patients from 1990 to 2002 at Children’s Hospital Boston were reviewed to identify patients with SR. The database was queried only with the key words “Schatzki ring,” and those identified were included in this study. Radiographic findings were confirmed by a single senior radiologist (CB), who was unaware of the clinical characteristics or final diagnosis of the patients. All contrast studies were performed with full column technique in the prone oblique position (6,7). SR was defined as a thin, intraluminal, symmetric, mucosal projection measuring 1 to 2 mm in thickness located at the gastroesophageal junction (1,2,6,8,13).

Medical records of patients with SR were reviewed to obtain demographic information. Presenting signs and symptoms, medical history, family history, allergic history, endoscopic findings, treatment, and clinical outcome were recorded. In some patients, pH monitoring of the distal esophagus was performed as previously described (10). Monitoring was defined as normal if the time during which the pH was less than 4 did not exceed 6% of the total time during a 24-hour period. (14,15).

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Histologic Assessment

Esophageal mucosal biopsy specimens were fixed in formalin, routinely processed, embedded in paraffin, cut serially in 5-micron sections, and stained with hematoxylin and eosin. Histologic classification of the biopsy specimens was performed as previously described (9). Quantitation of intraepithelial eosinophil number was performed by two authors (GTF and KB), who independently counted the number of eosinophils in each specimen in five separate high power fields (HPF) in the area with the densest inflammatory infiltrate. Data were expressed as the mean number of eosinophils per HPF (Nikon Optiphot-2, Plan 40× lens). The distribution of eosinophils within the squamous epithelium was also assessed. Measurements of the basal zone thickness and papillary length were made only on specimens in which at least three well-oriented papillae could be identified. Measurements were considered abnormal if there was basal zone hyperplasia greater than 20% of the total epithelial thickness or lengthening of the papillae to > 75% of the epithelial height (9). Superficial layering of eosinophils was diagnosed when there was a preferential concentration of eosinophils in the upper third of the esophageal epithelium. Microabscesses of eosinophils were diagnosed when there was a cluster of four or more eosinophils, typically near the mucosal surface (9,10). All clinical and histopathologic analyses were performed by investigators who were blinded to the patient’s history and clinical diagnosis.

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Diagnostic Criteria

Patients with SR were divided into two groups based on histologic findings as described here.

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Group A (eosinophilic esophagitis)

This group consisted of patients with: greater than 15 eosinophils/HPF in the squamous epithelium with or without superficial layering or eosinophil microabscesses; histologic esophagitis unresponsive to a minimum of 4 weeks of treatment with a proton pump inhibitor administered twice daily; and absence of eosinophilia in gastric and duodenal biopsy specimens.

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Group B (peptic esophagitis)

This group consisted of patients with: basal zone hyperplasia >20% of the total epithelial thickness or elongation of the epithelial papillae to >75% of the epithelial height; >3 but <15 eosinophils/HPF; and histologic response to antacid therapy.

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Statistical Analysis

Univariate statistics are presented as mean ± standard deviation. We used Mann-Whitney U test to compare patients with EE and those with peptic esophagitis. χ2 was used to compare proportions. The analysis was done with the use of SPPS for Windows (SPSS, Chicago, IL).

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RESULTS

Eighteen patients with SR were identified (15 male and 3 female; mean age, 15.8 ± 0.8 years). Dysphagia with food impaction was the most common symptom (Table 1). The average duration of symptoms before evaluation was 2.6 ± 0.4 years.

TABLE 1

TABLE 1

After examination of the histologic data, two groups of patients with SR were clearly defined. Group A (n = 8) had EE and group B (n = 10) had peptic esophagitis, as defined above (Table 2). Eosinophil microabscesses and superficial layering were seen in mucosal biopsies of 7 and 8 patients with EE, respectively. Comparisons of the clinical characteristics of Groups A and B are shown in Table 1. Of the other clinical characteristics, including food impaction, allergic history, peripheral eosinophil number, and family history of allergy, no significant differences were identified.

TABLE 2

TABLE 2

Although SR was diagnosed by validated radiologic criteria (2,6,8,13), a typical SR was not seen endoscopically in any of the patients in Group A and was recognized in 7 (70%) patients in Group B (P < 0.001). (Table 2). This finding suggests that in some patients, SR is only intermittently present. Gross mucosal features consistent with EE, such as furrowing and exudates, were seen more often in Group A than in Group B (P < 0.06).

A summary of the radiographic similarity and the endoscopic and histologic differences between Groups A and B is shown in Tables 1 and 2, as well as in Figures 1 (Group A) and 2 (Group B) that depict the features of each group. This figure series presents specimens from one patient in Group A and one patient in Group B. A clearly defined SR is seen in the radiographs in panels 1A (Group A) and 2A (Group B). In contrast, the endoscopic appearances show distinct differences. In Figure 1B, furrows and exudates are evident, but the SR is absent. In contrast, the esophagus of the patient from Group B shows a loss of vascular pattern and a circumferential thin membranous ring in the distal esophagus. The squamous epithelium of the patient from Group A contains a large number of eosinophils (44 ± 9 per HPF) (Fig. 1C) compared with a paucity of eosinophils in an obviously inflamed epithelium in the patient from Group B (Fig. 2C).

FIG. 1.

FIG. 1.

FIG. 2.

FIG. 2.

Nine patients had pH monitoring of the distal esophagus (4 in Group A; 5 in Group B). Results of pH probe monitoring were normal in EE patients who had a mean percent monitored time with pH < 4 of 2.0% ± 1.1%. In contrast, monitoring was abnormal in Group B patients whose mean percent time with pH <4 was 12.6% ± 2.9% (P < 0.01 group A v group B).

All patients were initially treated with proton pump inhibitors. Seven patients from Group B also underwent fluoroscopic guided esophageal balloon dilatation. Of the seven patients who underwent dilatation, five had total symptom remission after dilatation and acid blockade, whereas two had only a partial response to the treatment. Of the three patients who did not undergo dilatation, two had total symptom remission, whereas the other one had a partial response after treatment with acid blockade. Therefore, after antireflux therapy with proton pump inhibitors and/or dilatation, seven (70%) Group B patients experienced complete symptom remission, and the remaining three patients had partial improvement. Follow-up endoscopy showed that in the asymptomatic group, 2/7 had normal biopsy specimens and 5/7 had improvement from severe and moderate esophagitis to mild histologic esophagitis.

After antireflux treatment, only two of eight (25%) patients in Group A had complete remission of symptoms, four of eight (50%) had partial improvement, and two of eight (25%) experienced no improvement. Endoscopic studies on the two patients with no symptoms still showed histologic evidence of moderate and severe esophagitis. From the 6/8 patients who continued to have symptoms after antireflux therapy, 2/6 received no specific therapy for EE and continued to have symptoms. In the other 4, specific therapy for EE was given, and all had complete remission of symptoms with dietary intervention (1), inhaled steroids (2), or oral prednisone (1). Repeat endoscopy showed healing of esophagitis in three patients and marked improvement from severe to mild esophagitis in one.

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DISCUSSION

We report the clinicopathologic features of a large series of children with radiographic evidence of SR and report for the first time that a significant subset of these patients have features of EE. Although most of the children with SR had peptic inflammation and a ring upon endoscopic investigation, we found that 44% of the children with SR did not have any endoscopic evidence of SR and had severe eosinophilic esophageal mucosal infiltrates. These findings suggest that the radiographic finding of SR may be a novel finding associated with severe eosinophilic inflammation of the esophagus.

Because SR is located at the squamocolumnar junction (4,5,13), the most widely accepted theory of its pathogenesis is that it is part of the spectrum of chronic mucosal inflammation resulting from acid reflux (8). However, this association between SR and acid reflux is not certain. For instance, patients with SR often have no symptoms or do not get relief from antireflux medications (8). Prospective studies have documented an association with reflux in fewer than two thirds of patients with SR (2,4,8). Patients with SR have a normal lower esophageal sphincter pressure, suggesting that SR does not develop in the setting of prolonged lower esophageal sphincter hypotension (16–18). In addition, the presence of esophageal inflammation varies from 27% to 45% (18,19), and studies using pH monitoring to correlate the presence of excess acid in the esophagus with SR have been unsuccessful (3). Jamieson et al. (3) showed that the distal esophagus of 32 patients with SR had a lower incidence of acid exposure by pH monitoring than did that of a control group (59%v 81%). Ott et al. (8) demonstrated in 48 patients with SR that only 31% had abnormal acid exposure. Therefore, although peptic inflammation may be associated with SR in some patients, it is likely that other mechanisms account for its development in many.

Our findings demonstrate that most children with SR had underlying peptic inflammation and provide additional evidence supporting a role for acid in the generation of this lesion. However, 44% of the children (Group A) had no evidence for peptic disease and had no SR visible during endoscopic examination. Key features separating this group of patients from those with peptic disease include lack of response to acid blockade, normal pH probe monitoring of the distal esophagus, esophageal exudates and furrows, and severe eosinophilic inflammation of the esophageal mucosa, all characteristic findings of patients with EE (9–11). These findings suggest that another mechanism may be responsible for the radiographic appearance of the SR. We speculate that SR in patients with peptic disease is formed by a plication of esophageal mucosa as suggested previously (20). In patients with EE, however, SR may represent edema or thickening of redundant, inflamed esophageal mucosa.

Our previous work supports this speculation because we have shown that eosinophilic inflammation associated with EE extends beyond the squamous epithelium and into the submucosa and muscularis propria of the esophagus (12). The infolding of redundant esophageal mucosa may occur because it is loosely attached to the underlying tissues, except at the squamocolumnar junction, where it is firmly adherent (20,21). The impetus for mucosal redundancy and ring formation is esophageal shortening, produced by the contraction of the longitudinal muscle (20). The ring appears and disappears as the longitudinal muscle of the esophagus contracts and relaxes (20). In an autopsy study of four patients with a radiologic SR, a well-demarcated gastroesophageal junction was seen, and there was no fixed ring. The SR could be reproduced by foreshortening the full thickness of the gastroesophageal junction (5,20,21). These two hypothesis on the pathogenesis (inflammation and plication) are not mutually exclusive. It is possible that the plication of the mucosa occurs more frequently when there is esophageal mucosal inflammation (1). The plication theory also could explain the intermittent nature of symptoms and the fact that SR may not be seen endoscopically in many patients (1–3,7). In the current series, the SR was seen in only 49% of patients. In previous adult series, Scharschmidt and Watts (2) reported that the ring was seen endoscopically in only 44% of 18 patients, and Jamieson et al. (3) reported that the ring was seen in only 59% of 32 patients.

The lack of visualization during endoscopy could be related to the possibility that not all radiologically demonstrated rings are fibrous in nature (1) or, particularly in patients with EE, that air insufflation may stent the redundant mucosa. Some authors have suggested that there are two types of SR, a more common intermittent type and a less common fixed type (20), with the former being detected almost exclusively by radiologic methods. The intermittent SR probably is produced by mucosal plication and is the type seen in our patients with EE, whereas patients with peptic esophagitis may to have the fixed type. This distinction is important because the therapy and long-term results of treatment may vary according to the type of SR that is found.

As in series of adults with SR and children with SR or EE (10–12), most of our patients were male, and the most common presentation was dysphagia and food impaction. Neither the symptoms nor upper gastrointestinal series allowed the clinical distinction between peptic esophagitis and EE. The dysphagia may be related to the ring, but dysphagia is also a prominent symptom in patients with EE without SR (11,12). We have reported, by using prolonged esophageal manometry, that children with EE have a higher percentage of ineffective peristalsis, high amplitude contractions (> 180 mmHg), and isolated contractions than do control subjects (22).

Although the endoscopic appearance of the esophageal mucosa was indicative of EE in cases of EE, we found it was not very specific, indicating the need to perform endoscopic biopsies. Our findings also suggest that when a radiographic SR is not seen during endoscopy, the possibility of EE needs to be considered, and esophageal biopsies are needed.

A limitation of this study is its retrospective nature. Not all patients had pH monitoring. In patients in whom it was performed, there was a significant difference in acid exposure between Groups A and B. For those without pH monitoring, the diagnosis was made by histologic criteria after the administration of acid blockers (9). To avoid bias, no clinical or endoscopic characteristics were known to those reviewing the histology. This allowed an unbiased allocation of patients into Groups A and B based on histology only. The differences between the two groups of patients were not evident until the data were analyzed.

In conclusion, we suggest that EE may play a role in the pathogenesis of some patients with radiologically diagnosed SR. EE is a condition (10–12) that is being recognized more frequently. A Shatzki ring may provide a radiologic clue to its presence and lead to earlier diagnosis and appropriate treatment.

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Keywords:

Schatzki ring; Eosinophilic esophogitis; Gastroesophageal reflux

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